1. Field of the Invention
This invention relates to compositions that may be used as pharmaceutical compositions, methods and kits, more particularly to improved pharmaceutical formulations for paclitaxel that include vitamin-E derivatives.
2. Description of Related Art
Paclitaxel is a unique diterpene anticancer compound derived from the bark of the Taxus brevifolia (Pacific yew) tree. A crude extract of the bark demonstrated antineoplastic activity in preclinical tumor screening 30 years ago as part of the National Cancer Institute""s (NCI""s) large-scale screening program. The active component of the extract, paclitaxel, was isolated and described by M. C. Wani et al, Plant antitumor agents, VI: The isolation and structure of Paclitaxel, a novel antileukemic and antitumor agent from Taxus brevifolia, J. Am. Chem. Soc. 93:2325-2327 (1971). This document, and all others referred to herein, are incorporated by reference as if reproduced fully below.
In 1979, Schiff and coworkers rekindled interest in the development of paclitaxel by demonstrating its novel mechanism of action. Paclitaxel stabilizes the tubulin polymer and promotes microtubule assembly, rather than inducing microtubule disassembly like the antimicrotubule agents colchicine, vincristine, and vinblastine. This stabilization results in the inhibition of the normal dynamic reorganization of the microtubule network. Encouraging response rates (complete and partial) have been reported in single-agent phase II studies of paclitaxel in breast cancer, previously untreated non-small-cell lung cancer, head and neck cancer, and refractory ovarian cancer.
Unfortunately, paclitaxel is poorly soluble in water (less than 0.01 mg/mL) and other common vehicles used for the parenteral administration of drugs. Certain organic solvents, however, may at least partially dissolve paclitaxel. However, when a water-miscible organic solvent containing paclitaxel at near its saturation solubility is diluted with aqueous infusion fluid, the drug may precipitate.
Solubilization of compounds with surfactants allows for dilution of saturated or near-saturated formulations. Consequently, researchers formulated paclitaxel formulations using 50% Cremophor EL/50% dehydrated alcohol (USP, United States Pharmacopoeia), diluted in NS normal saline or D5W (5% dextrose in water) to a final concentration of 5% Cremophor EL and 5% dehydrated alcohol or less, for the intravenous administration of the drug to humans in early clinical trials. (Cremophor EL; Badische Anilin und Soda Fabrik AG [BASF], Ludwigshafen, Federal Republic of Germany). Paclitaxel for injection concentrate is currently available from Bristol-Myers Squibb Co. (New York, N.Y.) in 30-mg (5-mL) single-dose vials. Each milliliter of formulation contains approximately 6 mg Paclitaxel, 527 mg of Cremophor EL, and 49.7% (vol/vol) dehydrated alcohol. This concentrated formulation must be further diluted with NS, D5W, D5NS (normal saline, 5% dextrose in water and 5% dextrose in normal saline) or D5W-R (Ringer""s solution with 5% dextrose in water) prior to administration. It has been noted that the Cremophor/Ethanol formulation of paclitaxel precipitates upon dilution with infusion fluid, and fibrous precipitates formed in some compositions during storage for extended periods of time. Additional information regarding Cremophor formulations of paclitaxel may be found in Agharkar et al., U.S. Pat. No. 5,504,102.
An unexpectedly high incidence of serious hypersensitivity reactions was noted in phase I studies of the paclitaxel/Cremophor formulations. D. M. Essayan et al., Successful Parenteral Desensitization to Paclitaxel, J. Allergy and Clin. Immun. 97:42-46 (1996). Studies have shown that the Cremophor EL vehicle induces histamine release and hypotension in dogs within 10 minutes of administration.
In January 1985, the NCI sent a letter to all phase I investigators using paclitaxel, directing them to increase the duration of paclitaxel infusions and to pretreat all subjects with antihistamines (both H-1 and H-2 receptor blockers) and steroids. The incidence of hypersensitivity reactions subsequently decreased. Because the infusion duration was increased and pretreatment medications were added at the same time, it was not possible to determine whether infusion rate or pretreatment was the important factor.
Further studies were carried out in which paclitaxel was administered after premedication with steroids (such as dexamethasone, prednisone and hydrocortisone), antihistamines (such as diphenhydramine), and H-2 receptor blockers (such as cimetidine or ranitidine), and the infusion time was extended to 24 hours in an attempt to eliminate the most serious allergic reactions. See Einzig, et al., Phase II Trial of Taxol in Patients with Metastatic Renal Cell Carcinoma, Cancer Investigation, 9:133-136 (1991); A. B. Miller et al., Reporting Results of Cancer Treatment, Cancer 47:207-214 (1981). Additional description of premedication techniques may be found in Carretta et al., U.S. Pat. No. 5,670,537.
There are other disadvantages to using Cremophor formulations as well. Polyvinylchloride (PVC) infusion bags and intravenous administration sets usually contain diethylhexylphthalate (DEHP) as a plasticizer to maximize component flexibility. DEHP leaches to some extent into aqueous infusion fluids and blood products that come in contact with PVC materials. Exposure of animals to chronic high doses (more than 100 mg/kg) of DEHP has resulted in toxic effects including growth retardation, liver weight increase, liver damage, testicular atrophy, teratogenicity, and carcinogenicity. Cosolvents and surfactants may increase the amount of plasticizer leached. Waugh and colleagues evaluated the quantities of DEHP extracted from PVC infusion devices by the commercially available paclitaxel formulation. Substantial quantities of DEHP were extracted by all formulation concentrations tested. Therefore, there is a substantial health risk to patients receiving paclitaxel in the commercially available formulation using conventional PVC-containing equipment.
There is therefore a need for improved formulations comprising paclitaxel, methods of treatment using these formulations and kits comprising these formulations, to overcome the stability problems and to alleviate the clinical side effects of conventional paclitaxel formulations as noted above and as known to one of skill in the art.
The present invention provides new and improved formulations of paclitaxel, methods of manufacturing these formulations, kits containing these formulations and methods of treating cancer patients using these formulations. The new and improved formulations include pharmaceutically acceptable, water miscible solubilizers other than Cremorphor which are believed to have improved long term stability and reduced adverse effects relative to existing formulations.
In one aspect of the present invention, a composition for delivering paclitaxel in vivo is provided, which comprises paclitaxel; a solvent; and a pharmaceutically-acceptable, water-miscible solubilizer selected from the group consisting of solubilizers having the general structures:
R1COOR2, R1CONR2, and R1COR2,
wherein R1 is a hydrophobic C3-C50 alkane, alkene or alkyne and R2 is a hydrophilic moiety. The solubilizer is selected such that it does not have a pKa less than about 6. Optionally, the solubilizer does not have a pKa less than about 7, more preferably not less than about 8. By designing the solubilizer to not have any acidic hydrogens, potential destabilization of paclitaxel catalyzed by anionic moieties may be reduced. Upon the addition of water, the solubilizer forms micelles within which the paclitaxel is solubilized in the aqueous solution.
The solubilizer may preferably be an ester (R1COOR2) derived from a lipophilic acid (R1COOH) that has been esterified with a hydrophilic alcohol (R2OH). Examples of the lipophilic acids (R1COOH) include long chain carboxylic acids such as lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, archidonic acid, and d-xcex1-tocopheryl acid succinate. Examples of hydrophilic alcohols (R2OH) include polyalcohols such as polyethylene glycols (PEG): PEG 300, 400, and 1000. In a preferred embodiment, the solubilizer is a water miscible vitamin E derivative, and is most preferably d-xcex1-tocopherol polyethylene glycol succinate (TPGS).
The solvent in the composition may be pharmaceutically acceptable, water miscible organic solvent that can dissolve both paclitaxel and the solubilizer. Examples of suitable solvents include alcohols such as ethanol, propylene glycol and benzyl alcohol; polyalcohols such as polyethylene glycol (PEG); and amides such as 2-pyrrolidone, N-methyl-pyrrolidone and N,N-dimethyl acetamide.
The concentration of paclitaxel in the composition may preferably range from about 5-20 mg/g, more preferably from about 8-15 mg/g, and most preferably from about 10-13 mg/g.
The concentration of solubilzer in the composition may preferably range from about 40-90%w/w, more preferably from
45-75%w/w and most preferably from 50-60%w/w.
The weight ratio of the solubilizer to the solvent may preferably be between about 90:10-40:50, more preferably between about 70:30-45:55, and most preferably about 50:50.
The weight ratio of paclitaxel to the solubilizer may preferably be between about 1:10-1:100, more preferably about 1:20-1:80, and most preferably about 1:30-1:70.
In a preferred embodiment, the composition further comprises an acidifying agent added to the composition in a proportion such that the composition has a resulting pH between about 3 and 5. The acidifying agent may be an organic acid. Examples of organic acid include ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid, formic acid, benzene sulphonic acid, benzoic acid, maleic acid, glutamic acid, succinic acid, aspartic acid, diatrizoic acid, and acetic acid. The acidifying agent may also be an inorganic acid, such as hydrochloric acid, sulphuric acid, phosphoric acid, and nitric acid.
Optionally, the solubilizer does not have a hydrogen with a pKa less than about 7, more preferably not less than about 8. By designing the solubilizer to not have any acidic hydrogens, potential destabilization of paclitaxel catalyzed by anionic moieties may be reduced.
The composition may be diluted into aqueous solution by adding saline or other infusion fluid for parenteral administration or intravenous injection.
The composition may optionally be incorporated into a pharmaceutical carrier suitable for oral administration. For example, the composition may be filled into a soft or hard gelatin capsule, or other oral dosage forms. In these oral formulations, polyethylene glycols such as PEG 300 and PEG400 may preferably be used as the solvent for solubilizing paclitaxel, and the concentration of the solvent may preferably be less than about 40%w/w in the finally formed semi-solid or solid composition. These oral formulations may be administered into a host in need thereof, such as a cancer patient.
In another embodiment, a composition is provided which is made by the acts comprising: providing paclitaxel; and combining the paclitaxel with a pharmaceutically-acceptable, water-miscible solubilizer selected from the group consisting of solubilizers having the general structures:
R1COOR2, R1CONR2, and R1COR2,
wherein R1 is a hydrophobic C3-C50 alkane, alkene or alkyne and
R2 is a hydrophilic moiety. The solubilizer is selected such that it does not have a pKa less than about 6.
In another aspect of the present invention, a pharmaceutical formulation for delivering paclitaxel in vivo is provided, which comprises water; and micelles comprising paclitaxel and a pharmaceutically-acceptable, water-miscible solubilizer forming the micelles, the solubilizer selected from the group consisting of solubilizers having the general structures:
R1COOR2, R1CONR2, and R1COR2,
wherein R1 is a hydrophobic C3-C50 alkane, alkene or alkyne and R2 is a hydrophilic moiety. The solubilizer is selected such that it does not have a pKa less than about 6.
The solubilizer may preferably be an ester (R1COOR2) derived from lipophilic acids (R1COOH) that are esterified with a hydrophilic alcohol (R2OH). Examples of the lipophilic acids R1COOH include long chain carboxylic acids such as lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, archidonic acid, and d-xcex1-tocopheryl acid succinate. Examples of hydrophilic alcohols (R2OH) include polyalcohols such as polyethylene glycols (PEG): PEG 300, 400, and 1000. In a preferred embodiment, the solubilizer is a water miscible vitamin E derivatives, and is most preferably d-xcex1-tocopherol polyethylene glycol succinate (TPGS).
The solubilizer contained in both the composition and the pharmaceutical formulation is an amphiphilic ester (R1COOR2), an amphiphilic amide (R1CONR2) or an amphiphilic ketone (R1COR2) which is capable of forming micelle in aqueous solution. Hydrophobic tails (R1) of the solubilizer aggregate with lipophilic paclitaxel while hydrophilic heads (R2) of the solubilizer self-associate in water. Paclitaxel is thus solubized by associating with the hydrophobic tails of the micelles in aqueous solution.
The weight ratio of paclitaxel to the solubilizer may preferably be between about 1:10-1:100, more preferably about 1:20-1:80, and most preferably about 1:30-1:70.
The pharmaceutical formulation or the composition may optionally further include an excipient added to the composition in an amount sufficient to enhance the stability of the composition. Examples of the excipient includes, but are not limited to, cyclodextrin such as xcex1-, xcex2-, and xcex3-cyclodextrin and modified, amorphous cyclodextrin such as hydroxy-substituted xcex1-, xcex2- and xcex3-cyclodextrin.
Another pharmaceutical formulation is also provided, which is made by the acts comprising: providing a stock compostion comprising paclitaxel, a solvent and a pharmaceutically-acceptable, water-miscible solubilizer selected from the group consisting of solubilizers having the general structures:
R1COOR2, R1CONR2, and R1COR2,
wherein R1 is a hydrophobic C3-C50 alkane, alkene or alkyne and R2 is a hydrophilic moiety, the solubilizer being selected such that it does not have a pKa less than about 6; and combining the composition with an aqueous solution, wherein, upon addition of the aqueous solution, the solubilizer forms micelles within which the paclitaxel is solubilized in the aqueous solution.
One of the advantages of the above-described pharmaceutical formulations and compositions is the use of a non-ionic, amphiphilic solubilizer for paclitaxel. Previously, destabilization of paclitaxel by free carboxylate anion in formulations of Cremorphor occurred. The use of an ester, an amide or a ketone reduces this destabilization. By stabilizing paclitaxel in the composition, the storage shelf life for the composition can be prolonged, while the potency or pharmaceutical activity of the pharmaceutical formulation can be enhanced.
Another advantage of the pharmaceutical formulation is that paclitaxel is entrapped within the micelles formed by the solubilizer. As a result, light-induced damage to paclitaxel may be reduced during the period of infusion.
A further advantage of the pharmaceutical formulation is that the aqueous solution contains paclitaxel-carrying micelles which remain physically and chemically stable. The formulation can be administered intravascularly without undue toxicity from undissolved drug or precipitates of the solubilizer.
In yet another aspect of the present invention, a kit containing a pharmaceutical formulation for delivering paclitaxel in vivo is provided, the pharmaceutical formulation comprising: water and micelles comprising paclitaxel and a pharmaceutically-acceptable, water-miscible solubilizer forming the micelles, the solubilizer having the general structures:
R1COOR2, R1CONR2, and R1COR2,
wherein R1 is a hydrophobic C3-C50 alkane, alkene or alkyne and R2 is a hydrophilic moiety, the solubilizer being selected such that it does not have a pKa less than about 6.
In yet another aspect of the present invention, a method for administering paclitaxel to a host in need thereof is provided.
In one embodiment, the method comprises: providing a pharmaceutical formulation comprising: water and micelles comprising paclitaxel and a pharmaceutically-acceptable, water-miscible solubilizer forming the micelles, the solubilizer selected from the group consisting of solubilizers having the general structures:
R1COOR2, R1CONR2, and R1COR2,
wherein R1 is a hydrophobic C3-C50 alkane, alkene or alkyne and R2 is a hydrophilic moiety, the solubilizer being selected such that it does not have a pKa less than about 6; and administering the pharmaceutical formulation in a therapeutically effective amount to a host in need thereof.
The method may be used for administering paclitaxel to patients. A wide variety of uses are known for paclitaxel including the treatment of malignant diseases such as cancer including, but not limited to, human ovarian cancer, breast cancer, malignant lymphoma, lung cancer, melanoma, and Kaposi""s sarcoma. Other uses of paclitaxel may be developed in the future. The present invention may also intended to be used in conjunction with these future uses of paclitaxel.
In another embodiment, the method comprises: administering to a patient having a disease associated with abnormal cell proliferation and angiogenesis a pharmaceutical formulation containing paclitaxel, vitamin E-TPGS (D-xcex1-tocopheryl polyethylene glycol succinate), and solvent.
According to the embodiment, paclitaxel is solubilized by vitamin E-TPGS in a solvent, such as ethanol and polyethylene glycol (PEG), to form a homogenous composition. A particular example of vitamin E-TPGS is vitamin E-TPGS 1000 (d-xcex1-tocopherol succinate esterified with PEG 1000).
Also according to the embodiment, the pharmaceutical formulation may further comprise an acidifying agent added to the formulation in a proportion such that the formulation has a resulting pH between about 3 and 5. The acidifying agent may be an organic acid including, but not limited to, ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acid, formic acid, benzene sulphonic acid, benzoic acid, maleic acid, glutamic acid, succinic acid, aspartic acid, diatrizoic acid, and acetic acid. The acidifying agent may also be an inorganic acid, including, but not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. An anhydrous organic acid may preferably be used in a composition that may be further formulated for oral administration, such as incorporation into soft or hard gelatin capsules, tablet or other oral dosage forms.
The amount of acid added to the formulation may be sufficient to adjust the pH of the formulation at preferably between about pH 3-6, more preferably between about pH 3.5-5, and most preferably between about pH 3-4.
The pharmaceutical formulation may optionally further include an excipient added to the composition in an amount sufficient to enhance the stability of the composition, maintain the product in solution, or prevent side effects associated with the administration of the inventive composition. Examples of excipients include but are not limited to, cyclodextrin such as xcex1-, xcex2-, and xcex3-cyclodextrin and modified, amorphous cyclodextrin such as hydroxy-substituted xcex1-, xcex2-, and xcex3-cyclodextrin. Cyclodextrins such as Encapsin(copyright) from Janssen Pharmaceuticals may be used for this purpose.
The pharmaceutical formulations described above can be used for delivering paclitaxel in vivo via various routes of administration. For example, the formulation may be administered or coadministered with other therapeutic agent(s) orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally. The formulation may also be administered or coadministered in slow release dosage forms.
In a particular embodiment, the method comprises: administering to the patient a pharmaceutical formulation comprising paclitaxel and vitamin E-TPGS at a dose of 0.1-50 mg/Kg, preferably 1-20 mg/Kg, more preferably 1-10 mg/Kg, and most preferably 2-8 mg/Kg. The administration may be repeated, preferably every two weeks, and more preferably every three weeks. This formulation may be administered parenterally or orally to patient having a disease associated with undesirable or uncontrolled cell proliferation or angiogenesis.
According to the present invention, paclitaxel formulated with vitamin E-TPGS may be administered parenterally at a dosage lower than the current clinical dosage of TAXOL(copyright): 135 mg/m or 9 mg/Kg for an adult, for example, at dose below 100 mg/m2 or 7 mg/Kg. Paclitaxel formulated with vitamin E-TPGS may also be administered to a cancer patient by infusion for 3 hours or a shorter time once every week at a dosage below 100 mg/m2, such as 80 mg/m2.
Optionally, a desensitizer may be administered to the patients in order to reduce any potential anaphylactic or hypersensitive responses such as allergic reactions, pain and suffering. Examples of desensitizer include, but are not limited to, steroids (such as dexamethasone, prednisone and hydrocortisone), antihistamines (such as diphenhydramine), and H-2 receptor blockers (such as cimetidine or ranitidine). The desensitizer is preferably administered to the patient prior to treatment with paclitaxel formulated with vitamin E-TPGS.
Also optionally, cytokines such as granulocyte-colony stimulating factor (G-CSF) may be administered (e.g., by daily subcutaneous injection) to the patient treated with paclitaxel formulated with vitamin E-TPGS, preferably 24 hours after the paclitaxel treatment to ameliorate myelosuppression effects of paclitaxel or to speed up recovery from myotoxicity.
A wide variety of antineoplastic agents may have a therapeutic additive or synergistic effect with paclitaxel formulated with vitamin E-TPGS. Such antineoplastic agents may be hyperplastic inhibitory agents that addictively or synergistically combine with paclitaxel formulated with vitamin E-TPGS to inhibit undesirable cell growth, such as inappropriate cell growth resulting in undesirable benign conditions or tumor growth. Examples of such antineoplastic agents include, but are not limited to, alkylating agents, antibiotic agents, antimetabolic agents, hormonal agents, plant-derived agents, and biologic agents.
Preferable indications that may be treated using paclitaxel formulated with vitamin E-TPGS include those involving undesirable or uncontrolled cell proliferation. Such indications include restenosis (e.g. coronary, carotid, and cerebral lesions), benign tumors, a various types of cancers such as primary tumors and tumor metastasis, abnormal stimulation of endothelial cells (atherosclerosis), insults to body tissue due to surgery, abnormal wound healing, abnormal angiogenesis, diseases that produce fibrosis of tissue, repetitive motion disorders, disorders of tissues that are not highly vascularized, and proliferative responses associated with organ transplants.